ABSTRACT: Identifying Autism Loci and Genes by Tracing Recent Shared Ancestry
Eric M. Morrow1,2,3,4,5,*, Seung-Yun Yoo1,2,4,5,*, Steven W. Flavell5,6, Tae-Kyung Kim5,6, Yingxi Lin5,6, Robert Sean Hill1,2,4,5, Nahit M. Mukaddes7, Soher Balkhy8, Generoso Gascon8,9, Asif Hashmi10, Samira Al-Saad11, Janice Ware5,12, Robert M. Joseph5,13, Rachel Greenblatt1,2, Danielle Gleason1,2, Julia A. Ertelt1,2, Kira A. Apse1,2,5, Adria Bodell1,2, Jennifer N. Partlow1,2, Brenda Barry1,2, Hui Yao1, Kyriacos Markianos1, Russell J. Ferland14, Michael E. Greenberg5,6 and Christopher A. Walsh1,2,4,5,†
To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that underlie learning. A subset of genes, including NHE9 (Na+/H+ exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of “homozygosity mapping” in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations.
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